The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

• DOI: 10.1016/j.celrep.2018.09.079
• Publication Date: 2018-10-23T23:06:01Z
• Authors: Alessandro Torgov...; Jan Michel Heger; Vasiliki Liaki; Jörg Isensee; Anna Schmitt; Gero Knittel; Arina Riabinska; Filippo Beleggia; Lucie Laurien; Uschi Leeser; Christian Jüngst; Florian Siedek; Wenzel Vogel; Niklas Klümper; Hendrik Nolte; Maike Wittersheim; Lars Tharun; Roberta Castiglione; Marcus Krüger; Astrid Schauss; Sven Perner; Manolis Pasparakis; Reinhard Büttner; Thorsten Persigehl; Tim Hucho; Grit Sophie Herte...; Björn Schumacher; Hans Christian Re...
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; QH301-705.5; Carcinogenesis; Gene Dosage; Apoptosis; Mice, Transgenic; Cell Cycle Checkpoints; Fibroblasts; Embryo, Mammalian; Epithelium; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cytoprotection; Drug Resistance, Neoplasm; Animals; Regeneration; Biology (General); Tumor Suppressor Protein p53; DNA Damage

Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression.